The goal of the proposed training program is to provide the applicant with the skills and advanced knowledge necessary to develop an independent translational research program focusing on the neuroendocrinology of cognitive aging and Alzheimer's disease (AD). This career development award will enable the applicant to achieve his ultimate career goal of independence as an academic investigator. The proposed educational enhancement and research experiences build on the applicant's solid background in neuroscience research, insulin metabolism, neuropsychology, aging, and dementia, and will facilitate his acquisition of the information and interdisciplinary research skills that are critical for the study of complex neurodegenerative diseases. The training program includes formal didactics (neuroendocrinology, biostatistics, research design), frequent consultation with expert mentors, and a research plan that examines the mechanistic relationship among insulin, norepinephrine, and working memory, which is compromised in early AD. Working memory, which refers to an active mental store of information, depends on activation of the dorsolateral prefrontal cortex. Both insulin and norepinephrine influence working memory. In monkeys, the alpha2A adrenergic receptor (AR) agonist guanfacine facilitates spatial working memory. In humans, insulin administration (while maintaining normal plasma glucose) increases spinal fluid norepinephrine levels and facilitates performance on tasks that activate the dorsolateral prefrontal cortex (e.g., Stroop interference and self-ordered pointing tasks). Thus, insulin's effects on frontal executive tasks may be mediated directly through insulin receptors or indirectly through alpha2A-AR stimulation. Two proposed studies will examine the singular and interactive effects of insulin and alpha2A-AR stimulation on working memory for healthy older adults and adults with AD, who have reduced working memory. Specifically, this work will test the hypotheses (Study 1) that insulin alone will facilitate working memory, the alpha2A-AR agonist guanfacine alone will facilitate working memory, and guanfacine will potentiate insulin's enhancing effects, and (Study 2) that insulin alone will facilitate working memory, the alpha2-AR antagonist yohimbine alone will impair working memory, and yohimbine will attenuate insulin's enhancing effects. Thus, these studies have the potential to elucidate the neurobiology of working memory. Of even greater significance, these studies may suggest novel treatment strategies to ameliorate working memory deficits, and thus offer the possibility of improved quality of life to adults with AD or other diseases associated with impaired working memory.